There is an unmet need to inhibit the key cancer promoting transcription factor MYC (both c-MYC and MYCN) that act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cell resistance, tumor growth and the control of antitumor immunity. To date, small molecule inhibitors of MYC have remained elusive. In our preliminary data, we developed a lead compound, SF2523 which displays potent orthogonal inhibitory activity against MYC by blocking PI-3 kinase (PI-3K) and the highly dominant regulator of epigenetic machinery, BRD4. Herein, we set out to develop SF2523 and other chemotypes through additional in silico crystal structure and NMR analysis and optimization in preparation for advanced preclinical studies for therapeutic application in Myc dependent cancers. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and more recently in the control of antitumor immunity. It is overexpressed in a subgroup of most human cancers resulting in resistance to PI-3K and other signaling pathway inhibitors. Both MYC and PI-3K are well- established onco-proteins that are confirmed drivers in a large number of tumor types. Moreover, BRD4 is rapidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance to kinase inhibition. Therefore, there is general consensus in the cancer biology arena that inhibition of BRD4 and/or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor cell transformation and resistance. Our innovative approach centers on our central hypothesis that a dual PI- 3K/BRD4 inhibitor, SF2523, will potently inhibit MYC activity by enhancing its degradation via PI-3K inhibition AND block MYC transcriptional activity via BRD4 inhibition. Our preliminary data supports our success in that we solved the crystal structure of SF2523 in the active site of BRD4 and determined the structure activity relationships (SAR) around dual PI-3K/BRD4 inhibitors designed by validated molecular modeling studies and demonstrated the safety of our dual-targeting single inhibitor versus the accumulated toxicity of using two separate inhibitors. Our preliminary studies support our specific aims which include: 1) SAR to optimize the dual inhibitory chemotype (Aim 1) built around our crystal structure and NMR analyses (Aim 2) in parallel with 2) the evaluation of safety, PK/PD modeling and antitumor efficacy of each oral optimized chemotype (Aim 3). The objective of our proposal is to advance the preclinical development and validation of this novel dual PI- 3K/BRD4 inhibitor, SF2523 or its derivative as a final drug candidate against PI-3K/MYC-driven malignancies with high mortality rates e.g. hepatocellular carcinoma (HCC) and squamous cell carcinoma of the head/neck (SCCHN) and obtain an optimized oral candidate for final development. Moreover, our aims seek to identify PI-3K and MYC tumor signatures which will define sensitivity to SF2523 as we move toward a Phase I clinical trial of this ?first in class? dual PI-3K/BRD4 inhibitory chemotype for individualized cancer therapeutics.